NM_020451.3:c.1645G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020451.3(SELENON):c.1645G>A(p.Val549Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,614,140 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 12 hom. )

Consequence

SELENON
NM_020451.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.78

Publications

10 publications found

Variant links:

Genes affected

SELENON (HGNC:15999): (selenoprotein N) This gene encodes a glycoprotein that is localized in the endoplasmic reticulum. It plays an important role in cell protection against oxidative stress, and in the regulation of redox-related calcium homeostasis. Mutations in this gene are associated with early onset muscle disorders, referred to as SEPN1-related myopathy. SEPN1-related myopathy consists of 4 autosomal recessive disorders, originally thought to be separate entities: rigid spine muscular dystrophy (RSMD1), the classical form of multiminicore disease, desmin related myopathy with Mallory-body like inclusions, and congenital fiber-type disproportion (CFTD). This protein is a selenoprotein, containing the rare amino acid selenocysteine (Sec). Sec is encoded by the UGA codon, which normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon, rather than as a stop signal. A second stop-codon redefinition element (SRE) adjacent to the UGA codon has been identified in this gene (PMID:15791204). SRE is a phylogenetically conserved stem-loop structure that stimulates readthrough at the UGA codon, and augments the Sec insertion efficiency by SECIS. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2016]

SELENON Gene-Disease associations (from GenCC):

rigid spine muscular dystrophy 1
Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics, G2P
SELENON-related myopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
congenital myopathy 4A, autosomal dominant
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
congenital fiber-type disproportion myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
desmin-related myopathy with Mallory body-like inclusions
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
rigid spine syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SELENON links:

ENSG00000255054 (HGNC:):

ENSG00000255054 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005793333).

BP6

Variant 1-25815590-G-A is Benign according to our data. Variant chr1-25815590-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00267 (406/152278) while in subpopulation EAS AF = 0.0108 (56/5162). AF 95% confidence interval is 0.00858. There are 2 homozygotes in GnomAd4. There are 196 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SELENON	NM_020451.3 link	c.1645G>A	p.Val549Met	missense_variant	Exon 13 of 13	ENST00000361547.7	NP_065184.2	Q9NZV5-1
SELENON	NM_206926.2 link	c.1543G>A	p.Val515Met	missense_variant	Exon 12 of 12		NP_996809.1	Q9NZV5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7 link	c.1645G>A	p.Val549Met	missense_variant	Exon 13 of 13	1	NM_020451.3	ENSP00000355141.2		Q9NZV5-1
ENSG00000255054	ENST00000527604.1 link	n.123+1412G>A		intron_variant	Intron 2 of 3	5		ENSP00000457066.1		H3BT81

Frequencies

GnomAD3 genomes

AF:

0.00265

AC:

403

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00618

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.0108

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.00170

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000367

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00272

AC:

679

AN:

249548

AF XY:

0.00284

show subpopulations

Gnomad AFR exome

AF:

0.00626

Gnomad AMR exome

AF:

0.000435

Gnomad ASJ exome

AF:

0.00437

Gnomad EAS exome

AF:

0.0125

Gnomad FIN exome

AF:

0.00167

Gnomad NFE exome

AF:

0.000874

Gnomad OTH exome

AF:

0.00149

GnomAD4 exome

AF:

0.00116

AC:

1689

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

905

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00684

AC:

229

AN:

33478

American (AMR)

AF:

0.000358

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00383

AC:

100

AN:

26136

East Asian (EAS)

AF:

0.0103

AC:

408

AN:

39700

South Asian (SAS)

AF:

0.00502

AC:

433

AN:

86258

European-Finnish (FIN)

AF:

0.00183

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000260

AC:

289

AN:

1111994

Other (OTH)

AF:

0.00184

AC:

111

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

102

204

306

408

510

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00267

AC:

406

AN:

152278

Hom.:

Cov.:

AF XY:

0.00263

AC XY:

196

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00623

AC:

259

AN:

41562

American (AMR)

AF:

0.000850

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3472

East Asian (EAS)

AF:

0.0108

AC:

AN:

5162

South Asian (SAS)

AF:

0.00394

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00170

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000367

AC:

AN:

68034

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00169

Hom.:

Bravo

AF:

0.00318

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00587

AC:

ESP6500EA

AF:

0.000358

AC:

ExAC

AF:

0.00298

AC:

360

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 25, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22426012) -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SELENON: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2017

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SEPN1-related disorder

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Eichsfeld type congenital muscular dystrophy

Benign:1

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Eichsfeld type congenital muscular dystrophy;C0546264:Congenital myopathy with fiber type disproportion

Benign:1

Feb 15, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.061

.;T;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.39

T;T;T;T

MetaRNN

Benign

0.0058

T;T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

-1.8

.;N;.;.

PhyloP100

1.8

PrimateAI

Benign

0.40

PROVEAN

Benign

0.67

N;N;N;.

REVEL

Benign

0.28

Sift

Benign

1.0

T;T;T;.

Sift4G

Benign

0.70

T;T;T;T

Polyphen

0.0030, 0.0050

.;B;B;.

Vest4

0.15

MVP

0.71

MPC

0.24

ClinPred

0.0021

GERP RS

-0.99

Varity_R

0.024

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over